Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1994 Jun;93(6):2379–2386. doi: 10.1172/JCI117244

Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation.

R Roubenoff 1, R A Roubenoff 1, J G Cannon 1, J J Kehayias 1, H Zhuang 1, B Dawson-Hughes 1, C A Dinarello 1, I H Rosenberg 1
PMCID: PMC294444  PMID: 8200971

Abstract

The cytokines IL-1 beta and TNF-alpha cause cachexia and hypermetabolism in animal models, but their role in human inflammation remains controversial. The relationship between in vitro cytokine production and metabolism was examined in 23 adults with RA and 23 healthy control subjects matched on age, sex, race, and weight. Body composition was measured by multicompartmental analysis of body cell mass, water, fat, and bone mass. Resting energy expenditure (REE) was measured by indirect calorimetry. Cytokine production by PBMC was measured by radioimmunoassay. Usual energy intake, physical activity, disability scores, medication use, and other confounders were also measured. Body cell mass was 13% lower (P < 0.00001), REE was 12% higher (P < 0.008), and physical activity was much lower (P < 0.001) in subjects with RA. Production of TNF-alpha was higher in RA than controls, both before and after stimulation with endotoxin (P < 0.05), while production of IL-1 beta was higher with endotoxin stimulation (P < 0.01). In multivariate analysis, cytokine production was directly associated with REE (P < 0.001) in patients but not in controls. While energy and protein intake were similar in the two groups and exceeded the Recommended Dietary Allowances, energy intake in subjects with RA was inversely associated with IL-1 beta production (P < 0.005). In this study we conclude that: loss of body cell mass is common in RA; cytokine production in RA is associated with altered energy metabolism and intake, despite a theoretically adequate diet; and TNF-alpha and IL-1 beta modulate energy metabolism and body composition in RA.

Full text

PDF
2379

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baracos V., Rodemann H. P., Dinarello C. A., Goldberg A. L. Stimulation of muscle protein degradation and prostaglandin E2 release by leukocytic pyrogen (interleukin-1). A mechanism for the increased degradation of muscle proteins during fever. N Engl J Med. 1983 Mar 10;308(10):553–558. doi: 10.1056/NEJM198303103081002. [DOI] [PubMed] [Google Scholar]
  2. Block G., Hartman A. M., Dresser C. M., Carroll M. D., Gannon J., Gardner L. A data-based approach to diet questionnaire design and testing. Am J Epidemiol. 1986 Sep;124(3):453–469. doi: 10.1093/oxfordjournals.aje.a114416. [DOI] [PubMed] [Google Scholar]
  3. Block G., Hartman A. M. Issues in reproducibility and validity of dietary studies. Am J Clin Nutr. 1989 Nov;50(5 Suppl):1133–1235. doi: 10.1093/ajcn/50.5.1133. [DOI] [PubMed] [Google Scholar]
  4. Borkan G. A., Norris A. H. Fat redistribution and the changing body dimensions of the adult male. Hum Biol. 1977 Sep;49(3):495–513. [PubMed] [Google Scholar]
  5. Cahill G. F., Jr Starvation in man. N Engl J Med. 1970 Mar 19;282(12):668–675. doi: 10.1056/NEJM197003192821209. [DOI] [PubMed] [Google Scholar]
  6. Cannon J. G., Nerad J. L., Poutsiaka D. D., Dinarello C. A. Measuring circulating cytokines. J Appl Physiol (1985) 1993 Oct;75(4):1897–1902. doi: 10.1152/jappl.1993.75.4.1897. [DOI] [PubMed] [Google Scholar]
  7. Cannon J. G., van der Meer J. W., Kwiatkowski D., Endres S., Lonnemann G., Burke J. F., Dinarello C. A. Interleukin-1 beta in human plasma: optimization of blood collection, plasma extraction, and radioimmunoassay methods. Lymphokine Res. 1988 Winter;7(4):457–467. [PubMed] [Google Scholar]
  8. Clowes G. H., Jr, George B. C., Villee C. A., Jr, Saravis C. A. Muscle proteolysis induced by a circulating peptide in patients with sepsis or trauma. N Engl J Med. 1983 Mar 10;308(10):545–552. doi: 10.1056/NEJM198303103081001. [DOI] [PubMed] [Google Scholar]
  9. Cohn S. H., Ellis K. J., Vartsky D., Sawitsky A., Gartenhaus W., Yasumura S., Vaswani A. N. Comparison of methods of estimating body fat in normal subjects and cancer patients. Am J Clin Nutr. 1981 Dec;34(12):2839–2847. doi: 10.1093/ajcn/34.12.2839. [DOI] [PubMed] [Google Scholar]
  10. Dewys W. D., Begg C., Lavin P. T., Band P. R., Bennett J. M., Bertino J. R., Cohen M. H., Douglass H. O., Jr, Engstrom P. F., Ezdinli E. Z. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med. 1980 Oct;69(4):491–497. doi: 10.1016/s0149-2918(05)80001-3. [DOI] [PubMed] [Google Scholar]
  11. Dinarello C. A., Lonnemann G., Maxwell R., Shaldon S. Ultrafiltration to reject human interleukin-1-inducing substances derived from bacterial cultures. J Clin Microbiol. 1987 Jul;25(7):1233–1238. doi: 10.1128/jcm.25.7.1233-1238.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dykman T. R., Gluck O. S., Murphy W. A., Hahn T. J., Hahn B. H. Evaluation of factors associated with glucocorticoid-induced osteopenia in patients with rheumatic diseases. Arthritis Rheum. 1985 Apr;28(4):361–368. doi: 10.1002/art.1780280402. [DOI] [PubMed] [Google Scholar]
  13. Eastgate J. A., Symons J. A., Wood N. C., Grinlinton F. M., di Giovine F. S., Duff G. W. Correlation of plasma interleukin 1 levels with disease activity in rheumatoid arthritis. Lancet. 1988 Sep 24;2(8613):706–709. doi: 10.1016/s0140-6736(88)90185-7. [DOI] [PubMed] [Google Scholar]
  14. Endres S., Cannon J. G., Ghorbani R., Dempsey R. A., Sisson S. D., Lonnemann G., Van der Meer J. W., Wolff S. M., Dinarello C. A. In vitro production of IL 1 beta, IL 1 alpha, TNF and IL2 in healthy subjects: distribution, effect of cyclooxygenase inhibition and evidence of independent gene regulation. Eur J Immunol. 1989 Dec;19(12):2327–2333. doi: 10.1002/eji.1830191222. [DOI] [PubMed] [Google Scholar]
  15. Fries J. F., Spitz P. W., Young D. Y. The dimensions of health outcomes: the health assessment questionnaire, disability and pain scales. J Rheumatol. 1982 Sep-Oct;9(5):789–793. [PubMed] [Google Scholar]
  16. Goddard D. H., Moore M. E. Common tests for rheumatoid factors: poorly standardized but ubiquitous. Arthritis Rheum. 1988 Mar;31(3):432–435. doi: 10.1002/art.1780310317. [DOI] [PubMed] [Google Scholar]
  17. Grunfeld C., Feingold K. R. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N Engl J Med. 1992 Jul 30;327(5):329–337. doi: 10.1056/NEJM199207303270506. [DOI] [PubMed] [Google Scholar]
  18. Grunfeld C., Wilking H., Neese R., Gavin L. A., Moser A. H., Gulli R., Serio M. K., Feingold K. R. Persistence of the hypertriglyceridemic effect of tumor necrosis factor despite development of tachyphylaxis to its anorectic/cachectic effects in rats. Cancer Res. 1989 May 15;49(10):2554–2560. [PubMed] [Google Scholar]
  19. Hellerstein M. K., Meydani S. N., Meydani M., Wu K., Dinarello C. A. Interleukin-1-induced anorexia in the rat. Influence of prostaglandins. J Clin Invest. 1989 Jul;84(1):228–235. doi: 10.1172/JCI114145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Heymsfield S. B., Bethel R. A., Ansley J. D., Nixon D. W., Rudman D. Enteral hyperalimentation: an alternative to central venous hyperalimentation. Ann Intern Med. 1979 Jan;90(1):63–71. doi: 10.7326/0003-4819-90-1-63. [DOI] [PubMed] [Google Scholar]
  21. Hochberg M. C., Chang R. W., Dwosh I., Lindsey S., Pincus T., Wolfe F. The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum. 1992 May;35(5):498–502. doi: 10.1002/art.1780350502. [DOI] [PubMed] [Google Scholar]
  22. Hoshino E., Pichard C., Greenwood C. E., Kuo G. C., Cameron R. G., Kurian R., Kearns J. P., Allard J. P., Jeejeebhoy K. N. Body composition and metabolic rate in rat during a continuous infusion of cachectin. Am J Physiol. 1991 Jan;260(1 Pt 1):E27–E36. doi: 10.1152/ajpendo.1991.260.1.E27. [DOI] [PubMed] [Google Scholar]
  23. Jacobsson L. T., Knowler W. C., Pillemer S., Hanson R. L., Pettitt D. J., Nelson R. G., del Puente A., McCance D. R., Charles M. A., Bennett P. H. Rheumatoid arthritis and mortality. A longitudinal study in Pima Indians. Arthritis Rheum. 1993 Aug;36(8):1045–1053. doi: 10.1002/art.1780360804. [DOI] [PubMed] [Google Scholar]
  24. Janoff E. N., Limas C., Gebhard R. L., Penley K. A. Cryptosporidial carriage without symptoms in the acquired immunodeficiency syndrome (AIDS) Ann Intern Med. 1990 Jan 1;112(1):75–76. doi: 10.7326/0003-4819-112-1-75. [DOI] [PubMed] [Google Scholar]
  25. Johnson J., Dawson-Hughes B. Precision and stability of dual-energy X-ray absorptiometry measurements. Calcif Tissue Int. 1991 Sep;49(3):174–178. doi: 10.1007/BF02556113. [DOI] [PubMed] [Google Scholar]
  26. Kotler D. P., Tierney A. R., Wang J., Pierson R. N., Jr Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr. 1989 Sep;50(3):444–447. doi: 10.1093/ajcn/50.3.444. [DOI] [PubMed] [Google Scholar]
  27. Mahowald M. W., Mahowald M. L., Bundlie S. R., Ytterberg S. R. Sleep fragmentation in rheumatoid arthritis. Arthritis Rheum. 1989 Aug;32(8):974–983. doi: 10.1002/anr.1780320806. [DOI] [PubMed] [Google Scholar]
  28. Michie H. R., Sherman M. L., Spriggs D. R., Rounds J., Christie M., Wilmore D. W. Chronic TNF infusion causes anorexia but not accelerated nitrogen loss. Ann Surg. 1989 Jan;209(1):19–24. doi: 10.1097/00000658-198901000-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Moldawer L. L., Rogy M. A., Lowry S. F. The role of cytokines in cancer cachexia. JPEN J Parenter Enteral Nutr. 1992 Nov-Dec;16(6 Suppl):43S–49S. doi: 10.1177/014860719201600602. [DOI] [PubMed] [Google Scholar]
  30. Moldawer L. L., Svaninger G., Gelin J., Lundholm K. G. Interleukin 1 and tumor necrosis factor do not regulate protein balance in skeletal muscle. Am J Physiol. 1987 Dec;253(6 Pt 1):C766–C773. doi: 10.1152/ajpcell.1987.253.6.C766. [DOI] [PubMed] [Google Scholar]
  31. Moore F. D. Energy and the maintenance of the body cell mass. JPEN J Parenter Enteral Nutr. 1980 May-Jun;4(3):228–260. doi: 10.1177/014860718000400302. [DOI] [PubMed] [Google Scholar]
  32. Paffenbarger R. S., Jr, Hyde R. T., Wing A. L., Hsieh C. C. Physical activity, all-cause mortality, and longevity of college alumni. N Engl J Med. 1986 Mar 6;314(10):605–613. doi: 10.1056/NEJM198603063141003. [DOI] [PubMed] [Google Scholar]
  33. Pierson R. N., Jr, Wang J., Colt E. W., Neumann P. Body composition measurements in normal man: the potassium, sodium, sulfate and tritium spaces in 58 adults. J Chronic Dis. 1982;35(6):419–428. doi: 10.1016/0021-9681(82)90056-x. [DOI] [PubMed] [Google Scholar]
  34. Pincus T., Callahan L. F. Taking mortality in rheumatoid arthritis seriously--predictive markers, socioeconomic status and comorbidity. J Rheumatol. 1986 Oct;13(5):841–845. [PubMed] [Google Scholar]
  35. Reid D. M., Kennedy N. S., Smith M. A., Tothill P., Nuki G. Total body calcium in rheumatoid arthritis: effects of disease activity and corticosteroid treatment. Br Med J (Clin Res Ed) 1982 Jul 31;285(6338):330–332. doi: 10.1136/bmj.285.6338.330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Roubenoff R., Kehayias J. J. The meaning and measurement of lean body mass. Nutr Rev. 1991 Jun;49(6):163–175. doi: 10.1111/j.1753-4887.1991.tb03013.x. [DOI] [PubMed] [Google Scholar]
  37. Roubenoff R., Roubenoff R. A., Ward L. M., Holland S. M., Hellmann D. B. Rheumatoid cachexia: depletion of lean body mass in rheumatoid arthritis. Possible association with tumor necrosis factor. J Rheumatol. 1992 Oct;19(10):1505–1510. [PubMed] [Google Scholar]
  38. Roubenoff R., Roubenoff R. A., Ward L. M., Stevens M. B. Catabolic effects of high-dose corticosteroids persist despite therapeutic benefit in rheumatoid arthritis. Am J Clin Nutr. 1990 Dec;52(6):1113–1117. doi: 10.1093/ajcn/52.6.1113. [DOI] [PubMed] [Google Scholar]
  39. Roubenoff R., Wilson P. W. Advantage of knee height over height as an index of stature in expression of body composition in adults. Am J Clin Nutr. 1993 May;57(5):609–613. doi: 10.1093/ajcn/57.5.609. [DOI] [PubMed] [Google Scholar]
  40. Saxne T., Palladino M. A., Jr, Heinegård D., Talal N., Wollheim F. A. Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum. 1988 Aug;31(8):1041–1045. doi: 10.1002/art.1780310816. [DOI] [PubMed] [Google Scholar]
  41. Schindler R., Clark B. D., Dinarello C. A. Dissociation between interleukin-1 beta mRNA and protein synthesis in human peripheral blood mononuclear cells. J Biol Chem. 1990 Jun 25;265(18):10232–10237. [PubMed] [Google Scholar]
  42. Snyder D. S., Unanue E. R. Corticosteroids inhibit murine macrophage Ia expression and interleukin 1 production. J Immunol. 1982 Nov;129(5):1803–1805. [PubMed] [Google Scholar]
  43. Svenson K. L., Lundqvist G., Wide L., Hällgren R. Impaired glucose handling in active rheumatoid arthritis: effects of corticosteroids and antirheumatic treatment. Metabolism. 1987 Oct;36(10):944–948. doi: 10.1016/0026-0495(87)90129-6. [DOI] [PubMed] [Google Scholar]
  44. Svenson K. L., Lundqvist G., Wide L., Hällgren R. Impaired glucose handling in active rheumatoid arthritis: relationship to the secretion of insulin and counter-regulatory hormones. Metabolism. 1987 Oct;36(10):940–943. doi: 10.1016/0026-0495(87)90128-4. [DOI] [PubMed] [Google Scholar]
  45. Symmons D. P. Mortality in rheumatoid arthritis. Br J Rheumatol. 1988;27 (Suppl 1):44–54. [PubMed] [Google Scholar]
  46. Tocco-Bradley R., Georgieff M., Jones C. T., Moldawer L. L., Dinarello C. A., Blackburn G. L., Bistrian B. R. Changes in energy expenditure and fat metabolism in rats infused with interleukin-1. Eur J Clin Invest. 1987 Dec;17(6):504–510. doi: 10.1111/j.1365-2362.1987.tb01149.x. [DOI] [PubMed] [Google Scholar]
  47. Tracey K. J., Wei H., Manogue K. R., Fong Y., Hesse D. G., Nguyen H. T., Kuo G. C., Beutler B., Cotran R. S., Cerami A. Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J Exp Med. 1988 Mar 1;167(3):1211–1227. doi: 10.1084/jem.167.3.1211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Vaisman N., Stallings V. A., Chan H., Weitzman S. S., Clarke R., Pencharz P. B. Effect of chemotherapy on the energy and protein metabolism of children near the end of treatment for acute lymphoblastic leukemia. Am J Clin Nutr. 1993 May;57(5):679–684. doi: 10.1093/ajcn/57.5.679. [DOI] [PubMed] [Google Scholar]
  49. WEIR J. B. DE B. New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol. 1949 Aug;109(1-2):1–9. doi: 10.1113/jphysiol.1949.sp004363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Warren R. S., Starnes H. F., Jr, Gabrilove J. L., Oettgen H. F., Brennan M. F. The acute metabolic effects of tumor necrosis factor administration in humans. Arch Surg. 1987 Dec;122(12):1396–1400. doi: 10.1001/archsurg.1987.01400240042007. [DOI] [PubMed] [Google Scholar]
  51. van der Meer J. W., Endres S., Lonnemann G., Cannon J. G., Ikejima T., Okusawa S., Gelfand J. A., Dinarello C. A. Concentrations of immunoreactive human tumor necrosis factor alpha produced by human mononuclear cells in vitro. J Leukoc Biol. 1988 Mar;43(3):216–223. doi: 10.1002/jlb.43.3.216. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES